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Blood ; 143(23): 2373-2385, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38452208

ABSTRACT

ABSTRACT: Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous; and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e-4 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.


Subject(s)
Dependovirus , Factor VIII , Genetic Therapy , Genetic Vectors , Hemophilia A , Liver , Animals , Dogs , Dependovirus/genetics , Hemophilia A/genetics , Hemophilia A/therapy , Genetic Vectors/genetics , Liver/metabolism , Liver/pathology , Male , Genetic Therapy/methods , Female , Factor VIII/genetics , Gene Transfer Techniques , Virus Integration , Transgenes , Disease Models, Animal
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